Recombinant Antigen Receptor Segmentation for T Cell Activation
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Solution Overview
Problem
Current recombinant antigen receptors, such as CARs, often activate T cells through non-physiological mechanisms, leading to unwanted side effects like tonic signaling and autoimmune reactions due to the fusion of antigen-binding domains with CD3, and require xenogenic sequences for functionality, which can trigger immune responses.
Innovation Solution
Development of recombinant antigen receptors with two peptide chains, each comprising variable regions and immunoreceptor signal transmission domains, forming antigen binding sites through intermolecular interaction, allowing activation through the endogenous CD3 complex without xenogenic sequences, thereby minimizing immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antigen-binding domains are fused with CD3 to activate T cells, then T cell activation is achieved, but non-physiological activation occurs leading to tonic signaling and autoimmune reactions
Solution Approach 1:
The antigen receptor is divided into separate peptide chains (first and second peptide chains) rather than being fused into a single construct. Each chain contains specific domains that independently contribute to antigen binding and signal transmission, allowing physiological activation without tonic signaling
Solution Approach 2:
The invention introduces an intermediary structure where the first and second peptide chains form antigen binding sites through intermolecular interactions. This intermediary mechanism enables physiological T cell activation by mimicking natural TCR structure and function, avoiding direct fusion with CD3 that causes pathological activation
2Reliability
If xenogenic sequences are included in recombinant antigen receptors for functionality, then receptor function is achieved, but immune responses are triggered
Solution Approach 1:
The peptide chains in the invention are designed to be homogeneous in origin (both from human T cell receptors), eliminating xenogenic sequences that would trigger immune responses. This homogeneity maintains full receptor functionality while avoiding immunogenicity issues
Solution Approach 2:
The invention copies the natural T cell receptor structure and composition, using only human-derived sequences identical to those found in endogenous TCRs. This copying approach ensures full functionality while eliminating the need for xenogenic sequences that cause immune rejection
3Device complexity
If single-chain antigen receptors are used, then structural simplicity is achieved, but physiological activation through endogenous CD3 complex is compromised
Solution Approach 1:
The receptor is segmented into multiple peptide chains rather than using a single-chain construct. This segmentation restores the ability to form proper antigen binding sites through intermolecular interactions and enables physiological activation through the endogenous CD3 complex
Solution Approach 2:
The invention creates a composite structure where first and second peptide chains combine to form functional antigen binding sites. This composite approach mimics the natural TCR heterodimer structure, enabling physiological activation while maintaining structural organization
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables targeted and physiological activation of T cells, reducing the risk of autoimmune reactions and improving the therapeutic efficacy by stabilizing antigen-antigen receptor-endogenous CD3 signal transduction, allowing for effective immune responses against specific antigens like tumor cells while avoiding off-target effects.
Implementation Method 1
the first domain from the first peptide chain forms together with one of the domains from the second peptide chain a first antigen binding site, and wherein the second domain from the first peptide chain forms together with the other domain from the second peptide chain a second antigen binding site
Implementation Method 2
an immunoreceptor signal transmission domain, in which each of the two domains on one peptide chain forms an antigen binding site with one of the domains on the other peptide chain
Data Source
AI summary
The present invention generally embraces the treatment of diseases by targeting cells expressing an antigen on the cell surface. In particular the invention relates to recombinant antigen receptors and uses thereof. T cells engineered to express such antigen receptors are useful in the treatment of diseases characterized by expression of one or more antigens bound by the antigen receptors.